At present Respiratory Distress Syndrome (RDS) affects around 1 in 6,800 people with Neonatal Respiratory Distress Syndrome (NRDS) occurring in 40,000 infants and Adult Respiratory Distress Syndrome (ARDS) in 150,000 adults in USA. The incidence of ARDS in developing countries like India is much higher around 20 per 1000 admissions in the intensive care unit. Meconium Aspiration Syndrome (MAS) affects 1-2% of all deliveries.
Lung surfactant is synthesized by alveolar type II cells and is a complex mixture of lipids (90%) and proteins (10%). The primary function of the lung surfactant is to lower the surface tension at the air-liquid interface, thus preventing alveolar collapse during end expiration and reducing the work of breathing. Rapid adsorption of pulmonary surfactant to the air-liquid interface is essential for normal breathing.
In inflammatory diseases and conditions of surfactant dysfunction like ARDS and acute lung injury, the alveoli are filled with a proteinaceous fluid rich in albumin and a large number of acute inflammatory cells. These agents inhibit the function of the endogenous surfactant. Samples of bronchoalveolar lavage fluid from ARDS patients have lower levels of dipalmitoylphosphatidylcholine (DPPC), phosphatidylglycerol and surfactant proteins as compared to healthy persons. Thus there appears to be a logical role of surfactant therapy in ARDS and acute lung injury including that due to acid aspiration. However, the results of large controlled clinical trials using presently available exogenous surfactants in ARDS have failed.
Pulmonary inflammation represents an important component in the development of lung injury and ARDS. Oxidative stress also contributes to surfactant dysfunction. Also, it is increasingly recognized that in ARDS, surfactants are dysfunctional due to their unfavorable interactions with albumin and other inhibitory agents like acids and research must be directed towards developing tailor made surfactants that overcome albumin inhibition. As alveoli are flooded with plasma proteins over the early stages of ARDS, endogenous, surfactant may be inactivated. Albumin and serum are known to inhibit surfactant function in acute lung injury by competitive adsorption and by decreased airway patency. Taeusch et al. have shown the detrimental effect of serum on the adsorption of lung surfactants (cf H. Taeusch, J. de la Sena, J. Perez-Gil, C. Alonso, J. Zasadzinski, Inactivation of pulmonary surfactant due to serum-inhibited adsorption and reversal by hydrophilic polymers: experimental., Biophys. J. 89 (2005) 1769-1779). A direct thinning of surfactant bilayers due to addition of 5 wt % albumin to bovine lung extract surfactant was observed by X Ray diffraction studies by Larsson et al. (cf. Larsson M, Nylander T, Keough K M W, Nag K. An X-Ray diffraction study of alterations in bovine lung surfactant bilayer structures induced by albumin. Chem. Phys. Lipids 2006; 144:137-145). Thus, there is a need to develop surfactants that have specific interactions with albumin that allow them to maintain high airway patency in the presence of albumin.
All clinical trials using surfactants designed for NRDS have failed in ARDS. One of the trials used aerosolised Exosurf, a synthetic surfactant that does not contain any surfactant-associated proteins, to patients with sepsis-induced ARDS for upto 5 days [cf Anzueto A, Baughman R, Guntupalli K, De Maria E, Davis K, Weg J et al. “An international randomized placebo-controlled trial evaluating the safety and efficacy of aerosolized surfactant in patients with sepsis-induced ARDS”. AM. J. Respir. Crit. Care Med. 1994; 149:A567 and Anzueto A, Baughman R P, Guntupalli K K, Weg J G, Wiedemann H P, Raventos A A, Lemaire F, Long W, Zaccardelli D S, Pattishell E N “Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome” N. Eng. J. Med. 1996; 334:1417-21).
No differences in oxygenation, ventilator-free days or mortality were observed between the surfactant-treated and placebo groups. Other trials using lusupultide (containing lipids and recombinant SP-C) when administered in doses of 50 mg PL/kg up to 4 times over 24 hours, to patients with ARDS due to a variety of aetiologies, did not show any difference in the ventilator free days or overall survival [cf Spragg R G, Lewis J F, Walmrath H D, Johannigman J, Bellingan G Laterre P F et al. Effect of recombinant surfactant protein C based surfactant on the acute respiratory distress syndrome. N. Eng. J. Med. 2004; 351 (9):884-892).
However, at present there are no effective surfactants available for therapy in ARDS and Acute Lung Injury (ALI). The present invention addresses these shortcomings as it can overcome the inhibition caused by albumin using a unique protein-free surfactant that forms non-lamellar phases
Further, meconium aspiration syndrome is a condition where there is a secondary inactivation of the surfactant due to the presence of meconium. There is a need to develop surfactants that can prevent the meconium induced inhibition and maintain airway patency in the presence of meconium.